Despite significant progress in the interruption of HIV-1 transmission from an infected mother to her infant in developed countries, it is estimated that daily 1,600 infants are infected perinatally worldwide. Thus, understanding the risk factors associated with other-to-infant transmission remains critically important for the development of improved strategies for the prevention of vertical transmission. Moreover, although therapy has improved significantly for HIV-1 infected children, many challenges remain for the optimization of treatment. In the initial 4 years of funding, my laboratory has made several important observations that have helped to elucidate the pathogenesis of HIV-1 vertical transmission and disease progression in children. Our findings strongly suggest that certain HIV-1 phenotypes and genotypes combined with host chemokine receptor and chemokine genotypes are critical for determining the risk for infection and subsequent disease progression. In this revised, competitive renewal application, we propose to build on these initial findings by focusing on the impact of host genotype on perinatal transmission and disease progression. The specific aims of this proposal are: 1. To determine the association of chemokine receptor and chemokine genotypes on HIV-1 perinatal and postpartum (breast milk) transmission in two cohorts of children from Sub-Saharan Africa; 2. To identify chemokine receptor and chemokine genotypes that impact on HIV-1 related disease progression in children; and 3. To identify host chemokine receptor and chemokine genotypes that impact on development of HIV-1 related neurocognitive impairment in children. The findings of this research will provide an improved understanding of the pathogenesis of HIV-1 infection of children and perinatal transmission, and help to develop improved treatment/prevention strategies.